The present invention relates to a direct transition metal catalyzed process for the preparation of a variety of multifunctional substituted 2H-indazoles or substituted 2H-azaindazoles of the formula (I) from 2-halo-phenylacetylenes or (2-sulfonato)phenyl-acetylenes and monosubstituted hydrazines.
Indazoles display a vide variety of biological activities and can be regarded as important structures in pharmaceutical research. The ability of the indazole scaffold to mediate an interaction with a variety of biological targets, is well-documented by a number of reports on the observed biological activity, as well as by the fact that several indazole based compounds are in development or marketed as drugs demonstrating that this heterocycle can be an important element of a valuable pharmaceutically active ingredient. Some examples of biological activities include anti-inflammatory activity (R. J. Steffan, E. Matelan, M. A. Ashwell, W. J. Moore, W. R. Solvibile, E. Trybulski, C. C. Chadwick, S. Chippari, T. Kenney, A. Eckert, L. Borges-Marcucci, J. C. Keith, Z. Xu, L. Mosyak, D. C. Harnish J. Med. Chem. 2004, 47, 6435-38).
Of course the use of indazoles or azaindazoles is not limited to the above-mentioned pharmaceutical application. For example it is well known that indazoles can be useful in numerous other applications, for example as plant growth regulators (Y. Kamuro, K. Hirai Chemical Regulation of Plants, 1982, 17, 65) or liquid crystals (C. Canlet, M. A. Khan, B. M. Fung, F. Roussel, P. Judeinstein, J.-P. Bayle New. J. Chem. 1999, 23, 1223) among others.
Indazoles exist in 3 isomeric forms as 1H-, 2H- and 3H-indazoles depending on the substitution pattern of the heterocyclic ring and though a number of syntheses have been developed for the formation of 1H-indazoles, no general protocol for the synthesis of 2H-indazoles exist.
Known processes for preparing substituted 2H-indazoles or substituted 2H-aza-indazoles (J. J. Song, N. K. Yee, Org. Lett., Vol. 2, No. 4, 2000, 519-521; L. D. Shirtcliff, T. R. Weakley, M. M. Haley, F. Köhler, R. Herges J. Org. Chem, 2004, 69, 6979-85) by direct N-arylation or N-alkylation inevitably yielded a mixture of N(1) and N(2) regioisomers with poor selectivity. The few methods available so far are multi-step processes often affording low yields and regioselectivities with a restricted substrate range and thus a poor cost-effectiveness and therefore of limited use but suffer from the same limitations as the traditional procedures mentioned above. Although numerous transition metal catalyzed protocols for the intermolecular cross-coupling between aryl halides and amides, amines, hydrazides and hydrazones have been reported, only three examples employing hydrazines exist. Buchwald et al. describes several examples of cross-coupling between monosubstituted, 1,1- and 1,2-disubstituted hydrazines with aryl bromides (S. L. Buchwald, S. Wagaw, O. Geis WO99/43643) using a palladium catalyst in toluene and tert-butoxide base to obtain the desired arylated hydrazines in moderate to good yields. A similar catalytic system was reported by Cacchi et al. for the cross-coupling of 1,1-dialkyl-substituted hydrazine-(LiCl2)2 adducts with aryl bromides in good yields (S. Cacchi, G. Fabrizi, A. Goggiamani, E. Licandro, S. Maiorana, D. Perdicchia Org. Lett. 2005, 2, 1497-1500). Vasilevsky and Prikhodko have employed hydrazine in a cross-coupling reaction with (2-chloro-5-nitrophenyl)arylacetylenes to afford 1H-indazoles in good yields (T. A. Prikhodko, S. F. Vasilevsky Russ. Chem. Bull. Int. Ed., 2001, 50, 1268-1273). The reaction proceeds by a palladium catalyzed domino coupling-cyclization reaction and the scope of the reaction is rather limited as only four examples were reported and only (2-chloro-5-nitrophenyl)arylacetylenes were employed. Furthermore, in the same communication Vasilevsky and Prikhodko also report a single example of the palladium catalyzed domino Sonogashira-cyclization reaction of 2-iodoarylhydrazine and 4-nitrophenyl-acetylene to afford 4-nitrobenzyl-1H-indazole in low yield. A single example of 2H-indazole formation in 30% yield by the same domino Sonogashira-cyclization reaction between N′-(2-iodophenyl)acetic hydrazide and 4-nitrophenylacetylene is also described in the report.
It has now been found that the disadvantages mentioned can be avoided by a direct, catalytic, mild, versatile and regioselective synthesis.
The object is achieved by starting from 2-halo-phenylacetylenes or (2-sulfonate)phenyl-acetylenes of formula II and monosubstituted hydrazines of formula III in the presence of a transition metal catalyst.